Molecularly Informed Clinical Trials

Cancer drug development is typically done in a series of clinical
trials that expand in numbers of participants and duration,
referred to as Phase I, II and III clinical trials. Phase II trials enroll
small numbers of patients to test whether an investigational
drug is effective at reducing tumor burden. On the other hand,
Phase III trials involve very large numbers of patients and take
more time to complete. These trials assume homogeneity in both
the patients and the tumors; however, we now know that they
are heterogeneous and multiple subpopulations exist, such as
the presence of different genetic mutations. By contrast, the
“Personalized Trial” approach recognizes the heterogeneous
nature of the disease at the outset of the trial and the possibility
that not every treatment will be effective for all patients.

In the clinical trial depicted above/below, patients are genetically
screened and randomized to one of several treatments. The goal
is to match experimental treatments with molecular subtypes of
disease and ultimately generate “biomarker signatures.”
Experimental agents are dropped early (red X) in Phase II trials if
they fail to benefit patients; however, treatments that show a
benefit for a particular group of patients continue to be assessed
in further clinical testing. There are numerous efficiencies in this
process that speed drug development, including having multiple
groups simultaneously receiving investigational agents and only
a single, common comparator. But the major efficiency is
enabling a Phase III trial that is an order of magnitude smaller
than in the traditional approach because it focuses only on the
responding patient population. Two trials employing these trial
designs are I-SPY 2 and BATTLE- 2.

In the I-SPY 2 trial, experimental therapies are given prior to
surgery, and response is determined by a series of MRI images
that track tumor size. Patients are genetically screened for a
number of biomarkers, and the researchers use that information
to generate a common biomarker “signature” for patients who
respond to a particular therapy. As the trial progresses, the
experience of patients that have completed the trial is used to
change the course of the trial while it is still active, rather than
waiting until it has completely ended.

The BATTLE- 2 trial aims to stratify advanced stage non-small-cell lung cancer patients genetically and determine outcomes in
real time. This trial randomly assigns non-small-cell lung cancer
patients to a targeted therapy and then follows patient response
as a function of their genotype. The results of the very similarly
structured, recently completed BATTLE trial suggest that this
approach will be successful at linking biomarker signatures to
drug response.

The BATTLE trials and the I-SPY 2 trial have given us a window
into the future of cancer clinical trials. They highlight how
cooperation between all stakeholders can lead to new flexible
clinical trials that more efficiently and more rapidly meet the
urgent needs of cancer patients. Continued collaboration is
required to develop other innovative clinical trial designs that
can expedite testing of new drug combinations and assess the
ability of therapies to prevent metastasis.